The present invention relates to neurology and pharmacology, and to drugs for treating or preventing problems in the central nervous system (CNS). These problems involve abnormally low levels of activity at n-methyl-D-aspartate (NMDA) receptors; this condition is called, "NMDA receptor hypofunction" (NRH).
The following Background sections provide introductory information on NMDA receptors and several other types of receptors on the surfaces of neurons in the central nervous system, and on various neurotransmitters and drugs that either stimulate or suppress activity at these neuronal receptors.
Glutamate (GLU) and Neuronal Glutamate Receptors
Glutamate (sometimes abbreviated as GLU) is one of the 20 common amino acids used by all living cells to make protein. Glutamate is the ionized form of glutamic acid, which is its predominant form in neutral solutions, at pH 7.
In addition to its role as a building block in proteins, glutamate also plays an entirely distinct and crucial role in the central nervous system (CNS) of higher animals, including mammals and birds. Within the CNS, glutamate serves as the predominant excitatory neurotransmitter (e.g., Olney 1987; full citations to books and articles are provided below). In a brief overview, this process can be summarized as follows. At a neuronal synapse (i.e., a signal-transmitting junction between two nerve cells), a molecule of glutamate is released by the signal-transmitting neuron. The glutamate molecule enters the fluid in the gap between the two neurons, and it quickly contacts the exposed portion of a "glutamate receptor" on the surface of the signal-receiving neuron. This receptor is a protein molecule that straddles the cellular membrane of the signal-receiving neuron. Upon being activated (or "excited") by the glutamate molecule, the glutamate receptor molecule changes its conformation in a manner which briefly opens an ion channel which passes through the cell membrane. Calcium (Ca.sup.++), sodium (Na.sup.+), and certain other types of ions immediately flow through the ion channel, thereby altering a chemical ionic gradient that normally exists across the membrane of the neuron. This activates the neuron, causing it to release its own neurotransmitters.
To reset the mechanism and get the transmitting and receiving neurons ready to handle another nerve signal, the ion channel quickly closes, and the glutamate receptor releases the glutamate molecule. It floats back into the synaptic fluid between the neurons, where a molecular transport system intercepts it and pumps it back inside the transmitting neuron. The signal-receiving neuron restores its normal chemical gradients and regains a "polarized" condition ready to receive another nerve signal by pumping the calcium and sodium ions that had entered the cell, back out of the cell. This entire process occurs within a few milliseconds.
Since glutamate is an amino acid that can function as an excitatory neurotransmitter inside the CNS, it is often called an "excitatory amino acid" (EAA). Another type of amino acid, aspartate (the ionized form of aspartic acid), can also function as an excitatory amino acid in the CNS; therefore, glutamate receptors are sometimes referred to as EAA receptors, since they can be triggered by either glutamate or aspartate. However, glutamate is used much more widely than aspartate as a neurotransmitter, and EAA receptors (including both NMDA and non-NMDA receptors, discussed below) are referred to herein as glutamate or GLU receptors.
Types of GLU Receptors: NMDA and non-NMDA Receptors
This invention directly involves NMDA receptors, which are one class of glutamate receptors, and alpha-2 adrenergic receptors. To understand the full meaning of these terms, several terms need to be defined, and NMDA receptors must be contrasted with two other types of glutamate receptors.
A "receptor" as used herein refers to a macromolecular binding site which is at least partially exposed on the surface of a cell, and which has specific and limited affinity for one or more fluid-borne molecules called "ligands" (these usually are neurotransmitters or hormones). When a ligand contacts an appropriate receptor, a brief binding reaction occurs which triggers or otherwise evokes a cellular response, such as activation and depolarization of a neuron. Most receptor molecules are proteins which straddle the membrane of a cell, with an external portion for binding reactions and an internal portion which helps carry out the cellular response that occurs when the receptor is activated by a ligand.
This is not a rigid definition, and different scientists sometimes use the term "receptor" inconsistently; for example, they may either include or exclude various additional components, such as an ion channel which is opened or closed by a receptor. All of the glutamate receptors relevant to the present invention are associated with ion channels and therefore are referred to as ionotropic receptors.
In pharmacological terminology, an "agonist" is a molecule which activates a certain type of receptor. For example, glutamate molecules and drugs such as NMDA act as agonists when they excite EAA receptors. By contrast, an "antagonist" is a molecule which prevents or reduces the effects exerted by an agonist at a receptor.
There are three distinct types of ionotropic glutamate receptors in the mammalian central nervous system. Although all three receptor types are normally triggered by exactly the same EAA neurotransmitters in the CNS (i.e., glutamate or aspartate), these different subtypes of glutamate receptors have been found by researchers to have different binding properties when certain types of drugs are used as probes to study neuronal activity.
One major class of GLU receptors is referred to as NMDA receptors, since they bind preferentially to NMDA, which is n-methyl-D-aspartate. This analog of aspartic acid normally does not occur in nature, and is not present in the brain; it is, however, a useful probe drug which is widely used by neurologists. When molecules of NMDA contact neurons having NMDA receptors, they strongly activate the NMDA receptors and act as a glutamate agonist, causing the same type of neuronal excitation that glutamate causes.
The second class of glutamate receptors is called kainic acid (KA) receptors, since they are activated by kainic acid. The third class of GLU receptors is referred to herein as QUIS/AMPA receptors, since they are activated by both quisqualic acid (and its ionized form, quisqualate) and by alpha-amino-3-hydroxy-5-methyl-4-isoxazole (abbreviated as AMPA). Until the mid-to-late 1980's, AMPA receptors were called quisqualate (QUIS) receptors; however, quisqualate also activates a different type of receptor called a metabotropic receptor, so the recent trend is to call QUIS-type EAA receptors by the name "AMPA" receptors. KA receptors and QUIS/AMPA receptors are more closely related to each other (both structurally, and by higher levels of cross-affinity to certain drugs) than to NMDA receptors, and they are often referred to collectively as non-NMDA receptors.
The NMDA receptor complex (which includes an ion channel) has a number of distinct binding sites (also called recognition sites), where several different substances can bind to and modify the action of glutamate. Thus, there are several different types of NMDA antagonists, each type being defined in terms of the binding site with which it interacts.
Competitive NMDA antagonists compete with glutamate at the glutamate binding site (which is also the NMDA binding site). The action of glutamate at this site promotes opening of the ion channel to allow Na.sup.+ and Ca.sup.++ ions to flow into the cell. Competitive antagonists block the action of glutamate at this site, and prevent opening of the ion channel; thus, they are often referred to as "closed channel blockers."Competitive NMDA antagonists being developed by drug companies are usually given acronyms or code numbers, and they include, but are not limited to, compounds such as CPP (Boast 1988), D-CPP-ene (Herrling 1994), CGP 40116 (Fagg et al 1989), CGP 37849 (Fagg et al 1989), CGS 19755 (Boast 1988 and Grotta 1994), NPC 12626 (Ferkany et al 1989), and NPC 17742 (Ferkany et al 1993). Other competitive NMDA antagonists include D-AP5 (D-2-amino-5-phosphonopentanoic acid), D-AP7, CGP 39551 (D,L(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid carboxyethyl ester), CGP-43487, MDL-100,452, LY-274614, LY233536, LY233053. Most of these agents have been shown to cause pathomorphological changes in the cerebral cortex of adult rats (Olney et al 1991; Hargreaves et al 1993), and all of them that have been tested in adult humans have been shown to cause psychotomimetic reactions such as hallucinations (Grotta 1994; Herrling 1994; Kristensen et al 1992).
There are also other sites in the NMDA receptor complex, located outside the ion channel, where glycine or certain types of polyamines can bind. Binding of glycine and polyamines to these sites exerts a cooperative action that assists glutamate in opening the ion channel. Agents that block the glycine or polyamine sites may have neuroprotective actions, comparable to competitive antagonists acting at the glutamate binding site, although only limited information is available concerning the neuroprotective potential of agents acting at the glycine or polyamine sites (Carter et al 1988). Glycine and polyamine site antagonists include but are not limited to kynurenic acid, CNQX, DNQX, 6,7-DCQX, 6,7-DCHQC, R(+)-HA-966, 7-chloro-kynurenic acid, 5,7-DCKA, 5-iodo-7-chloro-kynurenic acid, MDL-28,469, MDL-100,748, MDL-29,951, L-689,560, L-687,414, ACPC, ACPCM, ACPCE, arcaine, diethylenetriamine, 1,10-diaminodecane, 1,12-diaminododecane, ifenprodil, and SL-82.0715 (for reviews and citations, see Rogawski 1992 and Massieu et al 1993).
Within the NMDA receptor ion channel, there is a site where phencyclidine (PCP) and several other drugs (including dizocilpine, ketamine, tiletamine, and CNS 1102) bind selectively. When these agents bind to the PCP site in the ion channel, they block ion flow through the ion channel, even if the channel otherwise remains open: thus, drugs that block activity at NMDA receptors by binding to the PCP site are sometimes referred to as "open channel blockers".
Dizocilpine is the most selective and effective non-competitive NMDA antagonist ever discovered; it is powerful and highly selective at the PCP binding site. The full chemical name is (+)-5-methyl-10,11-dihydro-5H-di[a,d]-cyclohepten-5,10-imine. The maleate salt of dizocilpine is commercially available to researchers under the name MK-801, and MK-801 has been investigated extensively for use as an antiepileptic and for preventing damage due to cerebral ischemia. It has, however, been shown, even at relatively low doses, to produce pathomorphological changes in cerebrocortical neurons in adult rats (Olney et al 1989).
Phencyclidine is a dissociative anesthetic, formerly used in human and veterinary medicine, that is illicitly abused as a hallucinogenic drug under the street name "angel dust". This drug can induce a psychosis which is clinically indistinguishable from schizophrenia, and it has been shown at relatively low doses to produce pathomorphological changes in various corticolimbic regions of the adult rat brain (Olney et al 1989, Corso et al 1994).
Ketamine is a dissociative anesthetic that is currently being used in human anesthesia, and is the only NMDA antagonist that is currently being used for anesthetic purposes. It is suitable for human anesthesia because it has an exceedingly short duration of action (usually about 15 minutes), which assures that its effects on the CNS, including adverse CNS effects, can be rapidly reversed by termination of ketamine administration. Despite its short duration of action, it occasionally produces an "emergence" reaction during recovery from anesthesia that is characterized by unpleasant dreams, confusion, agitation, hallucinations, and irrational behavior. Ketamine has recently been studied for its psychotomimetic effects and has been described as an agent that produces symptoms in normal humans that are indistinguishable from the symptoms of psychosis and thought disorder seen in schizophrenia (Krystal et al 1994). Ketamine also has been shown to cause pathomorphological changes in the cerebral cortex of adult rats (Olney et al 1989).
Tiletamine, also used in veterinary medicine as an anesthetic, is another non-competitive NMDA antagonist which acts at the PCP binding site. It has also been shown to cause pathomorphological changes in the cerebral cortex of adult rats (Olney et al 1989).
Toxic Effects of Excessive NMDA Activity; Utility of NMDA Antagonists
Excessive activation of NMDA receptors by endogenous glutamate is thought to play a major role in a number of important CNS disorders. In an acute crisis such as a stroke or CNS trauma, and in certain other events such as severe epileptic seizures, the cellular transport mechanism that removes glutamate almost immediately from the synaptic fluid, and pumps it back inside a neuron for subsequent re-use, can run out of energy to drive the glutamate clearance process. If this occurs, excessive glutamate begins to accumulate in the synaptic fluid between neurons. If glutamate molecules are not being removed from synapses at adequate rates, they begin to repeatedly and persistently excite glutamate receptors on signal-receiving neurons. This drives the receptor-bearing neurons into a state of hyper-excitation which can kill the neurons, through a process called "excitotoxicity" (e.g., Olney 1990, Choi 1988, Choi 1992).
Excessive activity at NMDA receptors can also severely aggravate neuronal damage caused by trauma (mechanical injury) to the brain or spinal cord. Many trauma victims suffer from a dangerous and potentially lethal increase in intracranial pressure, which involves water flowing into neurons in an effort to sustain osmotic balance as charged ions flow into the neurons during neuronal excitation. Elevated intracranial pressure is a major cause of morbidity and mortality in CNS trauma victims, and NMDA antagonists are potentially useful in reducing intracranial pressures following such crises.
As used herein, the term "acute insult to the central nervous system" includes short-term events which involve or pose a threat of neuronal damage mediated by excitotoxicity or other forms of excessive stimulation of neurons by glutamate. This includes ischemic events (which involve inadequate blood flow, such as a stroke or cardiac arrest), hypoxic events (involving inadequate oxygen supply, such as drowning, suffocation, or carbon monoxide poisoning), trauma in the form of mechanical or similar injury, certain types of food poisoning which involve an excitotoxic poison such as domoic acid, and seizure-mediated neuronal degeneration, which includes several types of severe epileptic seizures. NMDA antagonists can help to protect neurons in the CNS against such damage (e.g., Olney 1990; Choi 1992), and a number of NMDA antagonists (i.e., drugs that can suppress excitatory activity at NMDA receptors) are actively under development by several major pharmaceutical companies.
In addition to neuronal damage caused by acute insults, excessive activation of glutamate receptors may also contribute to more gradual neurodegenerative processes leading to cell death in various chronic neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), AIDS dementia, Parkinson's disease and Huntington's chorea (Olney 1990). It is considered likely that NMDA antagonists will prove useful in the therapeutic management of such chronic diseases.
Excessive activation of NMDA receptors is also responsible for the generation of "neuropathic" pain, a type of pain which is sometimes called "neurogenic pain" or "wind-up" pain (Woolf et al 1989; Kristensen et al 1992; Yamamoto and Yaksh 1992). Neuropathic pain is a chronic condition in which NMDA receptors in neural pain pathways have become "kindled" to an abnormally high level of sensitivity so that they spontaneously convey nerve messages that the patient perceives as pain even though no painful stimulus has been inflicted. By mechanisms that are poorly understood, pathological changes associated with diabetes are conducive to the generation of neuropathic pain, a condition known as "diabetic neuropathy". One of the distinguishing characteristics of neuropathic pain is that morphine and related pain-killing drugs which are effective in controlling other types of pain are usually ineffective in controlling neuropathic pain (Backonja 1994). Several recent reports indicate that NMDA antagonists can prevent or ameliorate neuropathic pain (Davar et al 1991; Mao et al 1992; Seltzer et al 1991; Neugebauer et al 1993; Kristensen et al 1992; Backonja et al 1994).
NMDA receptor activation has also been implicated as a mechanism underlying the development of tolerance to various potentially addictive drugs. "Tolerance" is used broadly herein, to include any or all of the following: dosage-type tolerance to a drug, which implies that a person must take an increasing amount of a drug in order to achieve the same level of sensations or therapeutic benefit; dependence upon a drug, which implies that a patient must continue taking a drug to avoid withdrawal symptoms; and, craving for a drug, which can include physiological and/or psychological cravings. A number of recent reports indicate that in animal studies, NMDA antagonists apparently prevented the development of tolerance to opiate analgesics (Marek et al 1991; Trujillo and Akil 1991; Ben-Eliyahu et al 1992; Tal and Bennett 1993) or benzodiazepine anxiolytics (L. Turski et al, PCT patent application WO 94/01094). It has also been reported that ibogaine, a drug known to have NMDA antagonist properties, can suppress the craving for cocaine (e.g., Sershen 1994).
NMDA Receptor Hypofunction (NRH)
The term "NMDA receptor hypofunction" (NRH) is used herein to refer to abnormally low levels of activity at NMDA receptors on CNS neurons. As discussed in the immediately following paragraphs, NRH can occur as a drug-induced phenomenon, following administration of an NMDA antagonist drug such as PCP or MK-801. It can also occur as an endogenous disease process; the Applicants have discovered that NRH appears to be an important mechanism responsible for symptom formation and pathological brain changes in idiopathic psychotic disorders such as schizophrenia.
NRH as a Drug-Induced Phenomenon: Both Beneficial and Detrimental
As described above under the heading, "Utility of NMDA Antagonists", when NRH is induced by NMDA antagonists (i.e., drugs that block or otherwise suppress activity at NMDA receptors), it can have several important beneficial effects. However, despite these beneficial effects, NMDA antagonists can also create serious detrimental side effects. As described in Olney et al 1989b, and in U.S. Pat. No. 5,034,400 (Olney 1991), NMDA antagonists have been shown to damage or even kill neurons located in a portion of the brain known as the posterior cingulate or retrosplenial (PC/RS) cortex and in certain other cerebrocortical and limbic regions of the animal brain. NMDA antagonists can also cause hallucinations, transient psychoses, and other psychotomimetic side effects in adult humans (for reviews see McCarthy 1981, and Olney and Farber 1994). Thus, a major obstacle to the use of NMDA antagonists as neurotherapeutic drugs lies in their potential for inducing adverse CNS side effects, including brain damage and psychosis.
It has been discovered by the Applicants that several types of drugs can act as "safener" agents to reduce or prevent the adverse side effects that can be caused by NMDA antagonists. Safener drugs previously described by the Applicants include at least three different classes:
(1) anticholinergic drugs which block the muscarinic class of cholinergic receptors, such as scopolamine, atropine, benztropine, trihexyphenidyl, biperiden, procyclidine, benactyzine or diphenhydramine; see Olney et al 1991, and U.S. Pat. No. 5,034,400 (Olney 1991);
(2) certain types of barbiturates, such as secobarbitol, which are called "direct GABA agonists" (Olney et al 1991). Unlike benzodiazepine drugs such as diazepam (sold under the trademark VALIUM), which can only increase the effects of naturally occurring inhibitory neurotransmitter called gamma-amino-butyric acid (GABA), direct GABA agonists can activate GABA type A (GABA.sub.A) receptors even in the absence of GABA.
(3) certain types of drugs that can bind to a class of receptors called sigma receptors (Farber et al 1993). These receptors are blocked by di(2-tolyl)guanidine and rimcazole, which are selective for sigma receptors, as well as other drugs such as haloperidol, thioridazine and loxapine, which interact with dopamine receptors as well as sigma receptors.
Despite the discoveries of those safening agents which can be used to reduce the toxic side effects of NMDA antagonists, there remains a need for improved treatments which take advantage of the beneficial effects of NMDA antagonists, while avoiding the adverse side effects that can be caused by NMDA antagonists. That type of improved treatment is one of the objects, and one of the disclosures, of this invention.
Based on several lines of evidence, discussed below, data gathered by the Applicants and by a number of other researchers indicate that the brain-damaging effects and the psychotogenic effects of NMDA antagonists apparently represent morphological and psychological manifestations of a single type of potentially toxic process, involving NMDA receptor hypofunction (NRH). It follows that any treatment effective in preventing the pathomorphological manifestations of drug-induced NRH in animals will also be effective in preventing at least some of the psychotic manifestations of drug-induced NRH in humans. In addition, as discussed below, any such treatment may have neurotherapeutic benefits in schizophrenia, in view of evidence identifying NRH as a mechanism that apparently causes or contributes to psychotic symptom formation and pathological brain changes in schizophrenia. Before these lines of evidence are presented in detail, another neuronal process needs to be analyzed, involving inhibitory neurotransmitter receptor systems and a potentially pathological process known as "disinhibition".
Inhibitory/Excitatory Transmitter Interactions; Disinhibition
It was mentioned above that in the CNS, glutamate is the principle type of excitatory neurotransmitter. Several other types of neurotransmitters also need to be discussed, since the interactions between glutamate and these systems are important to this invention.
Another major type of excitatory neurotransmitter molecule is acetyl choline (abbreviated as ACh). Like glutamate receptors, there are several different types of ACh receptors on neurons, which are divided into "muscarinic" and "nicotinic" classes of ACh receptors. The muscarinic class of ACh receptors is further subdivided into the m1, m2, m3, m4, and m5 subclasses. When a molecule of ACh contacts an ACh receptor on a neuron, this triggers a signal transduction process involving certain "second messenger" systems within the neuron, the net result being that a higher state of electrical activity is induced; this is another way of saying that the neuron is excited by ACh.
In the mammalian brain there also is a type of neurotransmitter receptor system referred to as the "sigma" receptor system. Although this system has been known for many years, progress has been slow in identifying the endogenous transmitter molecule that activates this system. However, recent evidence indicates that a certain peptide molecule that is abundantly contained in certain CNS neurons, called neuropeptide Y (NPY), has an important role in modulating the function of sigma receptors. The effects of NPY on the sigma receptor system are excitatory.
Therefore, in the brain circuitry that is relevant to the present invention, there are three excitatory transmitter receptor systems (glutamate, ACh, and sigma) and three excitatory transmitter molecules (glutamate, ACh and NPY).
In addition to the above three excitatory transmitter systems, there are also transmitter systems in the CNS that are primarily, or in some cases exclusively, inhibitory. The predominant inhibitory transmitter in the CNS is GABA (gamma-amino butyric acid). This inhibitory transmitter has important interactions with the glutamate excitatory system in many neural circuits within the CNS. Neurons that contain GABA and release GABA as an inhibitory transmitter are called GABAergic neurons.
In the particular neural circuitry relevant to the present invention (depicted in a simplified schematic manner in FIG. 1) glutamate is released in tiny amounts but on a continuous basis, by synapses that emerge from a neuron labelled as GLU neuron 10 in FIG. 1. Glutamate molecules being released by synapses which emerge from neuron 10 react with and activate NMDA receptors on the surfaces of three GABAergic neurons 20, 30, and 40 (as well another NMDA receptor on the surface of a norepinephrine (NE) neuron 50, as discussed below). This slow and steady release of GLU by neuron 10 provides a steady continuous driving force that keeps the GABAergic neurons 20, 30, and 40 in a constant state of activity, resulting in continuous release of GABA onto GABA inhibitory receptors on three different types of excitatory neurons, namely neurons that release glutamate (neuron 70), ACh (neuron 80), or NPY (neuron 60). Thus, glutamate, via its driving action on GABAergic inhibitory neurons, exerts "tonic inhibition" (the word "tonic" implies that it maintains a constant level of inhibitory tone) which restrains the activity of three separate excitatory pathways which use glutamate, ACh, and NPY as excitatory transmitters.
This represents an important principle (and an apparent paradox) of CNS activity, in which an excitatory neurotransmitter such as glutamate can cause suppression, rather than excitation, of neuronal activity. This is important not only for physiological functions in the CNS, but for understanding a mechanism called "disinhibition" which can contribute to dysfunction and degeneration of neurons in drug-induced or endogenous disease processes involving NMDA receptor hypofunction (NRH). Specifically, if the NMDA receptors which govern GABAergic neurons 20, 30, and 40 in FIG. 1 are blocked by an NMDA antagonist drug or rendered hypofunctional by a disease process, then the ability of neuron 10 to tonically inhibit the three excitatory neurons 60, 70, and 80 (via GABAergic neurons 20, 30, and 40) is lost. This loss of glutamate-mediated control is referred to herein as "disinhibition" of the inhibitory control mechanism that normally protects pyramidal neuron 90. When disinhibition occurs due to NMDA receptor hypofunction, all three excitatory neurons 60, 70, and 80 can begin to hyperstimulate and injure or kill PC/RS neuron 90.
All three of the excitatory neurons 60, 70, and 80 are coupled via axons to a pyramidal neuron 90, located in the posterior cingulate or retrosplenial (PC/RS) cortex of the brain. If all three of the excitatory neurons 60, 70, and 80 begin firing simultaneously, they can overstimulate pyramidal neuron 90 and begin pushing it to the point where it becomes so exhausted that it begins to suffer serious damage and eventually dies from overstimulation. The pyramidal neuron 90 is shown as having three different types of excitatory receptors: (1) kainic acid receptors, a type of non-NMDA glutamate receptor; (2) m3 receptors, a type of acetyl-choline muscarinic receptor; and, (3) sigma (.sigma.) receptors, which are believed to be triggered by neuropeptide Y (NPY). The presence of all three types of excitatory receptors on pyramidal neurons is supported by the experimental evidence in Example 6.
The schematic depiction in FIG. 1 also depicts an inhibitory neuron 50, located in the brain stem, which normally secretes norepinephrine (NE) into the forebrain via long fibrous processes, upon being stimulated by glutamate. This additional regulatory mechanism is described in more detail below.
The highly simplified schematic depiction in FIG. 1 indicates that a single glutamate-releasing neuron 10 interacts with all four inhibitory neurons 20, 30, 40, and 50. This is shown merely to avoid excessive clutter in the drawing; in the extraordinarily complex circuitry of the brain of a higher animal, thousands and possibly millions of glutamate-releasing neurons will interact to sustain tonic inhibition of neuronal circuits involving thousands and possibly millions of inhibitory neurons. The important point is that many and perhaps most of these interactions are mediated by glutamate release and NMDA receptors, and the tonic inhibition circuitry can be suppressed and rendered incompetent by NMDA antagonist drugs, or by endogenous NRH in certain disease processes, as occur in schizophrenia.
Similarly, PC/RS neuron 90 merely represents one of thousands or millions of neurons which are at risk due to NMDA receptor hypofunction, and the neurons at risk are scattered widely throughout a number of different corticolimbic regions of the brain. The PC/RS cortical region is the focal point of the histological examinations described in the Examples because it is typically one of the most consistently and heavily damaged areas; however, this is not meant to imply that it is the only area damaged or at risk.
The circuit diagram in FIG. 1, which was developed on the basis of recent experiments by the Applicants, is not disclosed in the prior art, and is part of the Applicants' invention. It can help provide a frame of reference to understand numerous published reports describing the injury or death of neurons in cerebrocortical and limbic brain regions following treatment of rats with NMDA antagonist drugs, and it can also help explain the schizophrenia-like psychotic reactions observed in humans following treatment with NMDA antagonist drugs. In addition, as will be discussed in the following paragraphs, it can explain mental disturbances and pathological brain changes in idiopathic psychotic illnesses such as schizophrenia.
NRH as a disease mechanism
It has been known for years that phencyclidine (PCP), ketamine, and certain other related drugs which recently have been shown to block NMDA receptors by acting at a PCP binding site in the NMDA receptor complex, cause psychotic reactions in humans which closely resemble the symptoms displayed by schizophrenics (Luby et al 1962; McCarthy 1981; Krystal et al 1994). It has also been shown recently that various other drugs that inhibit NMDA receptor activity by binding to different sites within the NMDA receptor complex can also cause similar psychotic reactions in humans (Kristensen et al 1992; Herrling 1994; Grotta 1994). Accordingly, the ability of NMDA antagonists to induce psychosis correlates not with action just at the PCP receptor site, but with their ability to reduce NMDA receptor activity to abnormally low levels, regardless of site or mechanism of action causing the reduced NMDA receptor activity. Therefore, several authors have hypothesized that impairment of the NMDA receptor system may be a causative or aggravating factor in the formation of psychotic signs and symptoms in schizophrenia (e.g., Javitt and Zukin 1991).
As used by most clinicians, the term "signs" refers to external manifestations that can be objectively assessed by a trained clinician, while "symptoms" generally refers to subjective complaints or comments made by a patient.
In recent years, there has been a tendency to subdivide the symptoms of schizophrenia into at least two categories, referred to as negative symptoms (e.g., levels of emotional withdrawal, blunted affect, autism, avolition, or anhedonia which extend beyond the normal ranges displayed by competent adults), and positive symptoms (e.g., hallucinations, which includes auditory and tactile as well as visual hallucinations, and delusions). Clinicians trained in the schizophrenia field have commented repeatedly that the mental disturbances induced by these NMDA antagonist drugs faithfully mimic both the negative and positive symptoms of schizophrenia (e.g., Javitt and Zukin 1991; Krystal et al 1994).
It has also been increasingly recognized in recent years that the brains of schizophrenic patients show evidence of pathomorphological changes in corticolimbic regions (Bogerts 1993), just as the brains of rats treated with NMDA antagonist drugs show evidence of pathomorphological changes in corticolimbic regions (Olney et al 1989; Corso et al 1994). These correlations have strengthened the belief that NRH, the mechanism by which NMDA antagonist drugs cause both psychotic and pathological brain changes, is the same mechanism causing these two types of changes in schizophrenia. It follows that any treatment that effectively prevents corticolimbic brain damage associated with the NMDA receptor hypofunction induced by NMDA antagonist drugs, is a promising treatment which, in at least some patients, will be able to prevent or ameliorate some or all of the psychotic symptoms (both positive and negative) and structural brain changes in schizophrenia.
Additional background information on the correlations between NMDA antagonists and schizophrenia is discussed in more detail in Olney and Farber 1995.
In the list of References, which begins on page 48, please modify the Olney and Farber 1995 ("in press") citation to read as follows:
Olney, J. W. and Farber, N. B., "NMDA antagonists as neurotherapeutic drugs, psychotogens, neurotoxins, and research tools for studying schizophrenia," Neuropsychopharmacology 13: 335-345 (1995)
The Adrenergic Transmitter System
This section provides background information on what was known about the alpha-2 adrenergic (.alpha.2) system prior to this invention. The involvement of this receptor system in reducing or preventing the toxic side effects of NMDA receptor hypofunction is part of the subject invention. Although a number of prior research reports indicate that NMDA receptor activity is linked somehow to various other receptors and neurotransmitters, none of the prior art suggested any involvement of .alpha.2 receptors in the neurotoxic side effects that can be caused by NMDA antagonists, or in the adverse CNS effects associated with NMDA receptor hypofunction.
An overview of the adrenergic neurotransmitter and receptor system is provided by Dahlstrom (pp. 11-14) and Dickinson and Lefkowitz (pp. 14-16) in Adelman's Encyclopedia of Neuroscience (1987). For more detailed reviews, see Ruffolo et al 1993 or Louis et al 1988. Briefly, norepinephrine (also called noradrenalin) is a neurotransmitter that is synthesized and secreted primarily by certain large neurons clustered in the brain stem. These neurons send long axonal processes to many regions of the forebrain, including the cerebral cortex, where they contact various forebrain neurons. Acting through these long axonal processes, the neurons which originate in the brain stem release norepinephrine into the forebrain. The effects of norepinephrine in the CNS are usually inhibitory and are often mediated by a mechanism involving inhibition of the release of other transmitters from neurons in the forebrain. In addition, some .alpha.2 receptors apparently have an auto-regulating function; when activated by norepinephrine, they apparently act to suppress the release of additional norepinephrine by neurons (Trendelenburg et al 1993).
Neuronal receptors which are triggered by norepinephrine or epinephrine (also called adrenalin) are called adrenergic receptors. These adrenergic receptors are divided into two classes, alpha and beta, which are subdivided into .alpha.1, .alpha.2, .beta.1, and .beta.2 classes. The .alpha.2 class is further subdivided into several subclasses, but no consensus nomenclature has yet emerged for these subclasses (see Ruffolo et al 1993). Norepinephrine is strongly active at all .alpha.1 and .alpha.2 adrenergic receptors, and has weak activity at .beta. receptors. Epinephrine has roughly equal activity at both .alpha. and .beta. adrenergic receptors.
Alpha-2 adrenergic receptors within the central nervous system are of interest herein; for convenience, these are referred to hereafter simply as .alpha.2 receptors. As noted above, norepinephrine (the natural neurotransmitter) activates both .alpha.1 and .alpha.2 adrenergic receptors. By contrast, several selective .alpha.2 agonist drugs (including clonidine, iodoclonidine, guanabenz, guanfacine, xylazine, lofexidine, medetomidine, dexmedetomidine, tizanidine, rilmenidine, azepexole, alpha-methyldopa, and alpha-methylnoradrenaline) have been discovered which activate .alpha.2 receptors with higher affinity than they have for .alpha.1 receptors. Most of these drugs which are of commercial interest are used clinically as anti-hypertensive drugs, to help reduce blood pressure in patients suffering from hypertension. Several have been used in human anesthesia, either alone or in combination with various opiates or inhalational anesthetics such as halothane (e.g., Doze et al 1989; Goodman and Gilman 1990, p. 308) and have been found to reduce the dose requirement for opiates or inhalational anesthetics. It has also been reported on the basis of animal studies that .alpha.2 agonist drugs can by themselves partially alleviate neuropathic pain (e.g., Puke and Wiesenfeld-Hallin 1993; Zeigler et al 1992; Danzebrink and Gebhart 1990).
Some .alpha.2 agonists have also been used in veterinary anesthesia. In veterinary medicine, a combination of ketamine (a dissociative anesthetic which has recently been shown to be an NMDA antagonist) with an .alpha.2 agonist such as xylazine or medetomidine has been administered to improve the duration and quality of anesthesia for animals and to reduce the dose requirement for ketamine (Verstegen 1989; Nevalainen et al 1989; Moens and Fargetton 1990).
At least two .alpha.2 agonists, clonidine and lofexidine, have also been tested by researchers to evaluate their ability to help reduce withdrawal symptoms in people addicted to cigarettes or opiates (e.g., Siegel et al 1985; Segal 1985; Green and Cordes 1989). Lofexidine is currently considered the agent of choice in Great Britain for attenuating opiate withdrawal symptoms, because of its reduced hypotensive side effects compared to clonidine (Washton et al 1983). While these drugs reportedly help reduce withdrawal symptoms in some recovering addicts, they are not generally considered effective in preventing the development of tolerance and physical dependence.
Clonidine has also been tested to see whether it can treat schizophrenia. As described in more detail below, the results were not satisfactory, and it is not in clinical use today as a treatment for schizophrenia.
None of these references disclose the use of an .alpha.2 agonist to block the neurotoxic side effects of an NMDA antagonist, nor do they suggest use of a combination of an .alpha.2 agonist with an NMDA antagonist which (unlike ketamine) has a sufficiently long duration of action to be of value for use as described herein. In addition, it was not heretofore recognized that the .alpha.2 receptor system has an inhibitory effect on neurons involved in the neurotoxic side effects caused by NMDA antagonists and by NMDA receptor hypofunction.
Accordingly, one object of the present invention is to disclose a method of using NMDA antagonist drugs in combination with .alpha.2 agonist drugs to reduce neuronal damage caused by acute insults to the CNS. By using an NMDA antagonist, excitotoxic and possibly other damage relating to excessive NMDA receptor stimulation can be reduced or prevented. By co-administering an .alpha.2 agonist drug with the NMDA antagonist, the neurotoxic side effects of the NMDA antagonist, such as hallucinations and damage to PC/RS cortical neurons, can be reduced or prevented.
Another object of this invention is to disclose a method of using NMDA antagonists in conjunction with .alpha.2 agonists for controlling neuropathic pain.
Another object of this invention is to disclose a method of using NMDA antagonists in conjunction with .alpha.2 agonists for preventing the development of tolerance to, dependence on, and craving for opiates and certain other drugs.
Another object of this invention is to disclose a method of using .alpha.2 agonist drugs to treat the clinical signs and symptoms of schizophrenia, and to prevent the pathological brain changes that accompany and aggravate schizophrenia.
These and other objects of this invention will be clarified and explained in the following summary and detailed description.